This new SPORE project seeks to take promising laboratory leads for lung cancer prevention, beginning with animal models, to proof of principle clinical studies. Our first efforts will explore electrophiles generated after metabolic activation of chemical carcinogens as well as reactive oxygen species. Both are major causes of malignancy. Cancer chemoprevention by induction of protective phase II proteins to counteract the effects of these carcinogens has gained considerable attention. Isothiocyanates have proved to be potent inducers of phase II proteins and compelling epidemiological evidence suggests that dietary isothiocyanates are linked with decreased incidence of lung cancer. Deciphering the downstream targets of isothiocyanates can help in developing these compounds for cancer chemoprevention. The genes for phase II proteins contain the antioxidant or electrophile response element (ARE), which regulate their basal and/or inducible expression. Nrf2, a member of the basic leucine zipper family plays a central role in activation of these genes by binding to ARE in response to its activation by chemopreventive agents. Our studies have shown that Sulforaphane, a naturally occurring isothiocyanate, acts as a potent activator of Nrf2. In this work, we used a microarray approach to identify Nrf2 targets in intestine, which included enzymes that detoxify a wide spectrum of electrophiles and tobacco specific carcinogens. The strategy of activation of Nrf2 for induction of phase II proteins recently has been shown to be effective among former smokers in a phase II b trial using anethole dithiolethione in lowering progression of pre-existing dysplastic lesions and appearance of new lesions. This proposal will focus on the hypothesis that activation of Nrf2 in lungs by Sulforaphane can lead to protection against lung cancer with the ultimate goal of developing this agent for clinical trials. The downstream targets of Nrf2 activation in lungs, identified using a genomics approach, will serve as biomarkers to monitor the efficacy of Sulforaphane for lung cancer chemoprevention in the NNK inducible A/J mouse lung cancer model. A small clinical trial will evaluate the efficacy of broccoli sprout extract, optimized for high amount Sulforaphane, to activate the Nrf2 pathway in individuals at high risk for lung cancer. Success in these studies will justify larger controlled studies in current and former smokers.